TW202400568A - Process for preparing cis-4-aminotetrahydrofuran-2-carboxylic esters - Google Patents

Abstract

The present invention relates to a novel process for preparing the salts of cis-4-aminotetrahydrofuran-2-carboxylic esters of the general formula (I).

Description

Method for preparing cis-4-aminotetrahydrofuran-2-carboxylate

The present invention relates to a novel method for preparing the salt of cis-4-aminotetrahydrofuran-2-carboxylate of general formula ( I ).

Cis-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride (CAS 1304126-28-0) of general formula ( I ) (where R ¹ = methyl) is an important building block of synthetic crop protection products ( WO 2012/130798, WO 2021/170464).

The first published synthetic route was proposed by Walker et al. (Synthesis 2011, 7, 1113-1119). The precursor used was 4-(tertiary butoxycarbonylamino)furan-2-carboxylic acid methyl ester (CAS 1170719-58-0, Wolter et al., Org. Lett. 2009, 11, 2804). However, 4-(tertiary butoxycarbonylamino)furan-2-carboxylic acid methyl ester cannot be economically produced on an industrial scale due to the high cost of the reagents used to prepare it, low yields, safety risks, and phosphate waste. feasible way to prepare. For example, this requires lithiation with secondary butyllithium (34% yield) and Curtius rearrangement with DPPA (diphenylphosphonic azide) ). Therefore, this route is not feasible for preparing cis-4-aminotetrahydrofuran-2-carboxylate on an industrial scale.

Furthermore, the synthesis via methyl 4-bromofuran-2-carboxylate (CAS 58235-80-6, WO 2021/170464) is expensive due to bromination and subsequent inefficient coupling with tertiary butylcarbamate (25% yield, WO 2021/170464), resulting in a large amount of waste.

In view of the above-mentioned prior art, the object of the present invention is to find a method for preparing cis-4-aminotetrahydrofuran-2-carboxylate, which is cost-effective and can be used on an industrial scale. It is also expected to obtain these compounds in an environmentally friendly manner, with high yields and with high purity, so that they do not need to undergo any further complicated purification, with the result that corresponding crop protection products can also be produced on an industrial scale.

The above objects (simple, cost-effective and industrial-scale preparation) are achieved by a process for the preparation of compounds of general formula ( I ) in salt form ( I ), wherein R ¹ is (C ₁ -C ₆ ) alkyl or (C ₃ -C ₆ ) cycloalkyl, characterized by a salt form of a compound of general formula ( II ) ( II ), in the presence of hydrogen and a rhodium catalyst, is converted into a salt form of a compound of general formula ( I ) in a solvent.

In a further embodiment, an acid is added to the reaction mixture.

The preferred definitions of the groups of the compounds of general formula ( I ) and ( II ) are as follows: R ¹ is (C ₁ -C ₆ ) alkyl.

Particularly preferred definitions of the groups of the compounds of general formulas ( I ) and ( II ) are as follows: R ¹ is CH ₃ .

Reactions to prepare compounds of formula ( I ) are shown in Scheme 1. Flowchart 1

The salt form of the compound of formula ( II ) is reacted in a solvent in the presence of hydrogen and a rhodium catalyst to form the salt form of the compound of general formula ( I ).

The pressure during the reaction is 1 to 100 bar, preferably 5 to 50 bar, particularly preferably 20 to 50 bar.

The temperature during the reaction is 0°C to 100°C, preferably 10°C to 80°C, particularly preferably 20°C to 40°C.

The catalyst used can be the following rhodium catalyst or a mixed catalyst composed of rhodium and one or more other metals, such as: Rh/C, Rh/Alox, Rh+Pd/C, Rh+Pt/C, Rh+ Cu/C, Rh+Ru/C; preferably: Rh/C, Rh+Pd/C, Rh/Alox; particularly preferably: Rh/C, Rh/Alox.

The loading amount of the precious metal on the carrier material of the catalyst used is 0.5%-10% of the precious metal; preferably, 1-5% of the precious metal is applied to the carrier material.

The amount of catalyst used is 0.1-10% by weight, based on the compound of formula ( II ); preferably, 0.5-5% by weight is used.

The amount of catalyst is calculated based on the dry weight of the catalyst. The catalyst can be used dry or wet. Water-wet catalysts can be washed to remove attached water prior to reaction in anhydrous solvents under an inert gas atmosphere. Alternatively, the water can be removed by azeotropic distillation with a suitable solvent. For example, toluene can be used in azeotropic distillation.

The catalyst can be reused or used once or preferably multiple times. Reactivation of the catalyst (for example, by appropriate washing) may facilitate its reuse, for example by washing with methanol or acidic methanol.

The compounds of formula ( II ) are used in the form of salts optionally with acids. Another acid or acid mixture can additionally be added to the reaction mixture. Preferably, the following acids are used together with the compound of formula ( II ) to form salts and/or as additives: HCl, H ₂ SO ₄ , MsOH, TfOH, TFA. Particularly preferred is HCl.

The molar ratio of acid to compound of formula ( II ) is 0-100%, preferably 0-10%.

Examples of suitable solvents and solvent mixtures are: R ¹ OH, R ¹ OH/toluene; R ¹ OH is preferred.

If the resulting compound of general formula ( I ) is in its salt form (eg, hydrochloride), the salt-free form can be obtained by treating the salt with a base (eg, triethylamine).

Compounds of general formula ( II ) are prepared according to WO 2022/018057. Method Description Example

The present invention is explained in more detail through the following examples, but the present invention is not limited thereto. Measurement method

The product is confirmed by ¹ H NMR spectroscopy and/or GC-MS (Gas Chromatography Mass Spectrometry).

NMR spectra were measured using a Bruker AV III 600.

GC-MS samples were measured using a Shimadzu GCMS-QP-2010-Ultra coupled with an additional FID (flame ionization detector). For this purpose, the sample was first evaporated, and then 1-10 mg of the dry sample was mixed with 250 μl of N-methyl-N-trimethylsilyltrifluoroacetamide for silylation. After a reaction time of 1-5 minutes, the sample was diluted with 1 ml of acetonitrile and measured.

Quantitative GC measurements were performed on a GC Agilent HB7890 B series. This technology is based on GC with FID detection, RTX-5 amine column and internal standard evaluation (internal standard: diethyl phthalate). Samples, reference standards and internal standards were dissolved in methanol. Preparation Example 1 of rac - cis -4- aminotetrahydrofuran -2- carboxylic acid methyl ester hydrochloride

In a 600 ml autoclave, 250 g of methanol solution containing 50 g of 4-aminofuran-2-carboxylic acid methyl ester hydrochloride (282 mmol) and 2.5 g of 5% Rh/C catalyst (dry, 1.22 mmol of Rh) were mixed and the autoclave was flushed 3 times with 5 bar of argon. The mixture was stirred under 50 bar of hydrogen and 50°C at 600 rpm for 16 hours. The autoclave was cooled and depressurized, and the mixture was filtered through a suction filter. The filtrate was concentrated to 123 g under reduced pressure, and 250 ml of toluene was added dropwise at 0°C. The mixture was stirred at 0°C for 30 minutes, and the precipitate was separated by suction filtration, washed twice with 15 ml of toluene, and dried under reduced pressure at 50°C. Yield: 36.2 g (66% of theoretical value) of target compound Purity (quantitative NMR): 93.5% of target compound ¹ H-NMR (DMSO-d6, 600 MHz): 1.95-2.04 (1H, m), 2.59- 2.67 (1H, m), 3.70 (3H, s), 3.75-3.85 (2H, m), 3.9-3.97 (1H, m), 4.45-4.52 (1H, t), 8.2-8.5 (3H, br) ppm . GC-MS (m/z): 217 [M+TMS], 202, 187, 172, 158, 142, 128, 116, 100, 89, 73, 59, 54 Example 2

A methanol solution of 25 g containing 5 g of 4-aminofuran-2-carboxylic acid methyl ester hydrochloride (28.2 mmol) was contacted with 0.15 g of 1% Rh+1% Pd/C in a 100 ml autoclave. The medium (50% water wet, 0.0073 mmol Rh and 0.007 mmol Pd) was mixed. The autoclave was flushed three times with 5 bar argon. Subsequently, the mixture was stirred at 600 rpm for 16 hours under a hydrogen pressure of 50 bar and 65°C. The autoclave was cooled and depressurized. The reaction mixture was weighed and the supernatant analyzed. Yield: 38.0 g of solution GC-FID: 76.1 area% target compound, 3.1 area% trans isomer Purity (quantitative NMR): 8.71% target compound, 0.47% trans isomer Yield (quantitative NMR): 64.7% of theoretical value Examples 3 to 9

The following experiments (Table 1) were performed with experimental procedures similar to Preparation Example 1: Table 1 Example Temperature (°C) H ₂ pressure (bar) Rh/C (5%) (wt%) ¹⁾ Rh/Alox (5%) (wt%) ¹⁾ Additives/Remarks Yield (%) ²⁾ 3 35 50 3 - 78 4 25 40 6 - 84 5 35 20 6 - 72 6 35 50 2 5 mol% HCl 83 7 35 40 2 5 mol% HCl 86 8 25 40 2 5 mol% HCl 95 9 25 40 2 5 mol% HCl, re-catalyst after acidic MeOH wash 94 10 25 30 2 - 86 11 25 30 2 Reuse catalyst after MeOH wash 84 12 25 10 6 Use water wet catalyst 86 13 30 40 2.5 1 mol% HCl, use dry catalyst 99 ^{3) 1)} Based on dry weight. ²⁾ Measure directly from the reaction solution by quantitative GC. ³⁾ Measure directly from the reaction solution by GC-FID.

without

without

without

Claims (9)

A compound of general formula ( I ) in the form of a prepared salt ( I ), wherein R ¹ is (C ₁ -C ₆ ) alkyl or (C ₃ -C ₆ ) cycloalkyl, characterized by a salt form of a compound of general formula ( II ) ( II ), in the presence of hydrogen and a rhodium catalyst, is converted into a salt form of a compound of general formula ( I ) in a solvent. The method of claim 1, characterized in that the groups of the compounds of general formulas ( I ) and ( II ) are defined as follows: R ¹ is (C ₁ -C ₆ ) alkyl. The method of claim 1, characterized in that the groups of the compounds of general formulas ( I ) and ( II ) are defined as follows: R ¹ is CH ₃ . A method according to any one of claims 1 to 3, characterized in that an acid is added to the reaction mixture. The method of claim 4, characterized in that another acid or acid mixture is added to the reaction mixture. The method of claim 4 or 5, characterized in that the acid added to the reaction mixture is HCl. The method of any one of claims 1 to 6, characterized in that R ¹ corresponds to methyl and the solvent is methanol. The method of any one of claims 1 to 7, characterized by using 0.1 to 10% by weight of catalyst (dry weight), based on the compound of formula ( II ). The method of claim 8 is characterized in that the catalyst used is Rh/C or Rh/Alox.